This proposal represents a close collaborative effort between the Jardetzky and Longnecker laboratories focusing on understanding Epstein-Barr virus (EBV) entry into target cells and on developing novel approaches to therapeutic intervention. The entry of EBV into both epithelial cells and B cells is directly relevant to the Program Announcement for AIDS-related malignancies. Both cell types are EBV target tissues in human hosts and the presence of EBV has been linked to cancerous growth in both tissues, in particular after the development of HIV/AIDS. Virus entry inhibitors have been identified for a number of viruses, including HIV, and we have demonstrated that EBV infection can also be blocked with high affinity peptide inhibitors. We hypothesize that inhibition of EBV entry may provide a therapeutic alternative in preventing or controlling the development of EBV-associated malignancies and/or pathologies in HIV/AIDS patients. We have developed a novel, mechanism-guided approach to designing EBV entry/membrane fusion inhibitors, based on understanding gH/gL glycoprotein structure and function, and demonstrated that gH/gL is a viable target for high affinity entry inhibitors. The current proposal continues this integrated research program on the EBV entry mechanism, addressing key hypotheses regarding the function and inhibition of the EBV gH/gL protein.